PROSTAGLANDIN SIGNALING IN FEMALE REPRODUCTION

描述(改编自申请人的描述)：环氧合酶 (COX)衍生的PG与生殖的许多方面有关，包括 排卵、植入和分娩，但可用信息有限 关于子宫中PG配体-受体信号的调节。这 申请将为首席调查员(PI)提供平衡的 教育和研究计划，以研究PG信号转导机制 在一位著名生殖科学家的指导下的小鼠。这个 建议得到具有分娩和产后护理专业知识的顾问的支持 生物学。 早产仍然是一个令人困惑的临床问题，尽管人们努力 找出并治疗早产的根本原因。申请人是 检查小鼠的分娩情况，以更好地了解 这一过程。初步结果表明：1)环氧合酶-1的明显表达 COX-2存在于足月子宫中；2)雌激素和孕激素受体 分别共定位于COX-1和COX-2表达的特定位点； 3)COX-2衍生的PG不能补偿COX-1-/-的分娩失败 小鼠，尽管外源性PGs是有效的；以及4)拯救胎儿PGs 携带野生型胚胎的COX-1/-受体小鼠的分娩失败 是胚胎移植的结果。总体而言，这些结果表明 分娩的多个方面汇聚在PG信号通路上。这个 卵巢类固醇及其受体在前列腺素信号转导中的作用 分娩的定义并不明确。因此，一种分娩的模式 包含这些配体和受体的关系是必需的。 这个应用程序的目标是识别PG的细胞来源 和它们的受体，检测卵巢类固醇对它们的影响 表达，并确定胎儿前列腺素在分娩过程中的作用 老鼠。中心假说是雌激素和黄体酮 PG配体水平的改变对分娩的显著影响 受体，以及足月子宫收缩和宫颈成熟 早产是通过不同的PG的不同动作来调节的 感受器。申请者将使用遗传和药理学方法来： 1)检查PG合成的来源和类固醇在足月或 早产；2)确定足月或早产时PG活动的部位 分娩；3)量化胎儿和胎盘来源的PG对足月分娩的贡献 和早产；以及4)确定早产是否发生在 PG缺陷小鼠以及这是否由不同于正常小鼠的途径调节 野生型老鼠。这项研究将使用COX-1-/-和cPLA2-/-小鼠，选择性COX 抑制剂，以及一种既定的早产引产方法。这个 这些实验的结果将加深对母婴关系的理解 PG信号，并可能为早熟或早熟提供新的见解 妇女中有功能障碍的分娩。

DESCRIPTION (Adapted from the applicant's description): Cyclooxygenase (COX)-derived PGs are implicated in many aspects of reproduction, including ovulation, implantation and parturition, yet limited information is available regarding the regulation of PG ligand-receptor signaling in the uterus. This application will provide the principal investigator (PI) with a balanced educational and research program to investigate mechanisms of PG signaling in the mouse under the mentorship of an established reproductive scientist. The proposal is supported by advisors with expertise in parturition and PG biology. Premature birth remains a perplexing clinical problem despite efforts to identify and treat the underlying causes of preterm labor. The applicant is examining parturition in the mouse to better understand the molecular basis of this process. Preliminary results show that: 1) distinct expression of COX-1 and COX-2 occurs in the term uterus; 2) estrogen and progesterone receptors co-localize to the specific sites of COX-1 and COX-2 expression, respectively; 3) COX-2-derived PGs do not compensate for parturition failure in COX-1-/- mice, although exogenous PGs are effective; and 4) fetal PGs rescue parturition failure in COX-1 -/- recipient mice carrying wild-type embryos resulting from embryo transfer. Collectively, these results suggest that multiple aspects of parturition converge on the PG signaling pathway. The effects of ovarian steroids and the receptors that transduce PG signals during parturition are poorly defined. Thus, a model for parturition that encompasses these ligand and receptor relationships is needed. The objective of this application is to identify the cellular source of PGs and their receptors, examine the influence of ovarian steroids on their expression, and determine the contribution of fetal PGs to parturition in the mouse. The central hypothesis is that estrogen and progesterone exert significant effects on parturition by altering the levels of PG ligands or receptors, and that uterine contractility and cervical maturation during term and preterm labor are mediated by the differential actions of distinct PG receptors. The applicant will use genetic and pharmacologic approaches to: 1) examine the source and steroid regulation of PG synthesis during term or preterm labor; 2) determine the sites of PG actions during term or preterm labor; 3) quantify the contribution of fetal and placental-derived PGs to term and preterm labor; and 4) determine whether preterm labor occurs in PG-deficient mice and whether this is regulated by different pathways than in wild-type mice. The study will use COX-1-/- and cPLA2-/- mice, selective COX inhibitors, and an established method for induction of preterm labor. The results of these experiments will enhance the understanding of maternal-fetal PG signaling, and are likely to provide new insights into premature or dysfunctional labor in women.